CN102356071A

CN102356071A - Novel alpha-(n-sulfonamido)acetamide compounds incorporating deuterium as inhibitors of beta amyloid peptide production a novel alpha-(n-sulfonamido) acetamide compound incorporating deuterium as inhibitor of beta amyloid peptide production

Info

Publication number: CN102356071A
Application number: CN2010800122954A
Authority: CN
Inventors: J.E.小斯塔雷特; K.W.吉尔曼; R.E.奥尔森
Original assignee: Bristol Myers Squibb Co
Current assignee: Bristol Myers Squibb Co
Priority date: 2009-03-19
Filing date: 2010-03-18
Publication date: 2012-02-15
Also published as: AR075903A1; US20100240719A1; US8044077B2; EP2408757B1; TW201038266A; WO2010107984A1; JP2012520896A; EP2408757A1

Abstract

The present disclosure provides novel deuterated alpha-(N-sulfonamido)acetamide compounds, their pharmaceutical composition, processes thereof and a method for the treatment of Alzheimer's disease, head trauma, traumatic brain injury, and/or dementia pugilistica and/or other conditions associated with ss-amyloid peptide.

Description

Mix deuterium α-(N-sulfonamido) acetamide compound as the novelty of beta starchy peptide to produce inhibitor

The cross reference of related application

The rights and interests that No. the 61/161st, 629, the U.S. Provisional Patent Application that the application requires to submit on March 19th, 2009.

Technical field

The present invention relates to a pharmaceutical properties and biological activity of deuterated (2R) -2 - [[(4 - chlorophenyl) sulfonyl] [[2 - fluoro-4 - (1,2,4 - ?

Figure 2010800122954100002DEST_PATH_IMAGE001

oxadiazol-3 - yl) phenyl] methyl] amino] -5,5,5 - trifluoro-pentyl amide compounds, their pharmaceutical compositions, their preparation and use.This new compound has the effect that unique inhibition A β peptide is produced; Thereby play a part to prevent that A β peptide and/or amyloid beta deposition thing from accumulating in brain; Can be used for treatment or delay the generation that alzheimer's disease (AD), Down's syndrome and mild cognitive damage, and a treatment wound, traumatic brain injury, boxer's dementia and/or other illness relevant with beta amyloid peptide.

Background technology

Alzheimer's disease (AD) is a kind of carrying out property neurodegenerative disease, and it begins with hypomnesis, develops into to comprise serious conscientiously damage, behavior change and hypokinesia (Grundman, M. etc., Arch Neurol. (2004) 61:59-66; Walsh, D. M. etc., Neuron (2004) 44:181-193).It is dull-witted common form, is the cause of death that is number three after cardiovascular diseases and the cancer.AD's is costly, comprises torment that patient and family suffer and patient and paramedic's reducing of the productivity.Still the incompetent at present methods of treatment that effectively prevents AD or reverse clinical symptom and potential physiopathology.

Make a definite diagnosis AD for dementia patients and need neural inflammatory spot and the number of neurofibrillary tangles and the histopathology evaluation (Consensus recommendation for the postmortem diagnosis of Alzheimer ' s disease. Neurobiol Aging (1997) 18:S1-2) of position based on postmortem.In the patient of trisomy 21 syndromes (Down's syndrome), observe similar variation.Patch mainly is made up of beta amyloid (A β) peptide; It is by amyloid precursor protein (APP) by β-position APP restriction endonuclease (BACE) progressively the albumen acyl separate cutting and produce the N-end; Produce the C-end and form (Selkoe, D. J. Physiol Rev. (2001) 81:741-766) by gamma-secretase.Gamma-secretase is a kind of transmembrane protein mixture, and it comprises slow-witted albumen, Aph-1, PEN-2 and senilism albumen-1 (PS-1) or senilism albumen-2 (PS-2) (Wolfe, M. S. etc., Science (2004) 305:1119-1123).PS-1 and PS-2 are believed to comprise the catalytic site of gamma-secretase.

A β 40 is (80-90%) forms of the maximum of synthetic A β, and A β 42 is and the related form the most closely of AD pathogenesis.Specifically, the variation in APP, PS-1 and the PS-2 gene causes rare familial AD, shows that A β 42 aggregates are main toxicity species (Selkoe, D. J., Physiol. Rev., (2001) 81:741-766).Evidence suggests the A β 42 in oligomeric protofibril and the born of the same parents in lysis, play an important role (Cleary, J. P. etc., Nat Neurosci. (2005) 8:79-84) at present.The suppressor factor that forms the enzyme (for example gamma-secretase) of A β 42 has been represented the regulation and control treatment of diseases medicine that might be used to treat AD.

Gamma-secretase also cuts multiple I type transmembrane protein (Pollack, S. J. etc., Curr Opin Investig Drugs (2005) 6:35-47) except that APP.Though most physiological significance it be unclear that in these cutting incidents; But the genetics evidence shows; Gamma-secretase cutting Notch protein is that essential (Science (1999) 284 (5415): 770-6 for Artavanis-Tsakonas, S. etc. for the Notch signal transduction; Kadesch, T.; Exp Cell Res. (2000) 260 (1): 1-8).In taking the rodent of inhibitors of gamma-secretase, the toxicity relevant (Searfoss, G. H. in stomach and intestine (GI) road, thymus gland and spleen, have been found with medicine; Jordan etc., J. Biol Chem. (2003) 278:46107-46116; Wong, G. T. etc., J. Biol Chem. (2004) 279:12876-12882; Milano, J. etc., Toxicol Sci. (2004) 82:341-358).These toxicity probably with the inhibition relevant (Jensen, J. etc., Nat Genet. (2000) 24:36-44) of Notch transduction.

Based on the toxic discovery of mechanism the problem whether inhibitors of gamma-secretase can reach acceptable therapeutic index has been proposed.The selectivity that has precedence over Notch processing, medicine kinetics, disposition of drug and/or tissue specificity pharmacodynamics suppresses A β and forms, and can influence the safety range of treatment.

Evidence shows, can prevent generation and development (Selkoe, D. Physiol. Rev. (2001) 81:741-766 of AD through the A β level in the inhibition gamma-secretase attenuating brain; Wolfe, M., J. Med. Chem. (2001) 44:2039-2060).The data about the effect of A β in other disease occurred, these diseases comprise mild cognitive damage (MCI), Down's syndrome, cerebral amyloid angiopathy (CAA), dementia with Lewy body (DLB), amyotrophic lateral sclerosis (ALS-D), inclusion body myositis (IBM) and the macular degeneration relevant with the age.Advantageously, suppress gamma-secretase with reduce compound that A β produces can be used for treating these or other with A β diseases associated.

The excessive generation of A β and/or removing minimizing can cause CAA (Thal. D. etc., J. Neuropath. Exp. Neuro. (2002) 61:282-293).In these patients, blood vessel amyloid beta deposition thing causes vascular wall degeneration and aneurysma, and they possibly be the reasons of 10-15% gerontal patient hemorrhagic stroke.With the same in AD, the variation in the gene of coding A β causes the form of CAA early onset thereof, is called the hematencephalon with Dutch type amyloidosis, and the mouse of expressing this variant protein can be developed the CAA similar with the patient.Compound with the target of gamma-secretase can reduce or prevent CAA specifically.

DLB demonstrates photis, vain hope and Parkinson's disease.Ironically, cause the sedimental familial AD variation of A β also can cause Louis body and DLB symptom (Yokota, O. etc., Acta Neuropathol (Berl) (2002) 104:637-648).In addition, sporadic DLB patient have with AD in similar A β settling (Deramecourt, V. etc., J. Neuropathol Exp Neurol (2006) 65:278-288).According to these information, A β causes the lewy body disease Li Tezheng among the DLB probably, so inhibitors of gamma-secretase can reduce or prevent DLB.

About 25% ALS patient has tangible dementia or aphasia (Hamilton, R. L. etc., Acta Neuropathol (Berl) (2004) 107:515-522).These patients' great majority (～60%) are known as ALS-D, and they contain and are mainly comprising the positive inclusion body (Neumann, M. etc., Science (2006) 314:130-133) of the proteic ubiquitin of TDP-43.About 30% ALS-D patient has amyloid plaque, with the A β consistent (Hamilton, R. L. etc., Acta Neuropathol (Berl) (2004) 107:515-522) that causes their dementia.These patients should use the amyloid preparation to differentiate, and might treat with inhibitors of gamma-secretase.

IBM is a kind of rare skeletal muscle degenerative disease relevant with the age.A β settling occurs in IBM muscle and APP from overexpression to muscle that in transgenic mice, introduce can make and reproduces aspect this disease several; This supports the effect (Murphy of A β in IBM; M. the commentary of P. etc., Neurology (2006) 66:S65-68).The compound that specificity is attacked gamma-secretase can reduce or prevent IBM.

In the macular degeneration relevant with the age, A β is confirmed to be one of several components of the born of the same parents' external sediment thing drusen under the retinal pigment epithelium (RPE) (Anderson, D. H. etc., Exp Eye Res (2004) 78:243-256).Recent research has shown potential contact the (Yoshida, T. etc., J Clin Invest (2005) 115:2793-2800) of A β and macular degeneration in the mouse.Found in AD patient that cataract increases (Goldstein, L. E. etc., Lancet (2003) 361:1258-1265) on A β deposition and the nuclear.The compound that specificity is attacked gamma-secretase can reduce or prevent the macular degeneration relevant with the age.

Based on the effect of Notch signal transduction in tumour takes place, the compound that suppresses gamma-secretase also can be used as therapeutical agent and is used to treat cancer (Shih, I.-M. is etc., Cancer Research (2007) 67:1879-1882).

The compound that suppresses gamma-secretase also can be used for treating with myelin and forms the relevant illness that goes down, for example multiple sclerosis (Watkins, T. A. is etc., Neuron (2008) 60:555-569).

The recent research of Georgetown University Medical Center researchist shows, inhibitors of gamma-secretase can prevent because the long-term damage that traumatic brain injury causes (Loane, D. J., etc., Nature Medicine (2009): 1-3).

Smith etc. disclose a series of sulfonamide compoundss in the International Patent Application WO of announcing on August 31st, 2,000 00/50391; They can work to regulate the generation of amyloid-beta; Can be used for treating multiple disease, especially alzheimer's disease and other disease relevant with the deposition of amyloid.

The Japanese Patent No. 11343279 that on December 14th, 1999 announced discloses a series of sulfonamide compoundss, and they are TNF-alpha inhibitors, can be used for treating autoimmune disease.

Parket etc. disclose a series of α as the amyloid-beta suppressor factor-(N-sulfonamido) acetamide derivative in the International Patent Application WO of announcing on July 3rd, 2,003 03/053912, they can be used for treating alzheimer's disease and other illness relevant with beta amyloid peptide.

The invention provides a kind of compound that can be used for treating alzheimer's disease and other illness relevant with beta amyloid peptide.

Summary of the invention

The present invention relates to a chemical formula I, deuterated (2R) -2 - [[(4 - chlorophenyl) sulfonyl] [[2 - fluoro -4 - (1,2,4 -

oxadiazol-3 - yl) phenyl] methyl] amino] -5,5,5 - trifluoro-pentyl amide compounds, their pharmaceutical formulations, and their use in inhibiting suffering from or susceptible to Alzheimer's disease (AD) or the β-amyloid peptide Patients with other diseases related to Aβ produced in the application, wherein the compound of formula I containing one or more deuterium atoms.

Figure 2010800122954100002DEST_PATH_IMAGE003

In one aspect of the present invention, as shown in Figure IA, deuterium is coupled to the oxadiazole ring.

Figure 2010800122954100002DEST_PATH_IMAGE005

In another embodiment, the present invention provides a pharmaceutical composition which contains pharmaceutically acceptable adjuvants, carriers or diluents in a therapeutically effective amount of deuterated (2R) -2 - [[(4 - chloro- phenyl) sulfonyl] [[2 - fluoro -4 - (1,2,4 -

oxadiazol-3 - yl) phenyl] methyl] amino] -5,5,5 - trifluoro pentaneamide.

In yet another embodiment, the present invention provides a method for the treatment, alleviation or delaying the β-amyloid peptide-related disease onset, in particular Alzheimer's disease, cerebral amyloid angiopathy, mild recognition known to damage and Down syndrome, the method comprising the conventional auxiliary agents, carrier, or diluent, administering a therapeutically effective amount of a deuterated (2R) -2 - [[(4 - chlorophenyl) sulfonyl] [[ 2 - fluoro -4 - (1,2,4 -

oxadiazol-3 - yl) phenyl] methyl] amino] -5,5,5 - trifluoro-pentyl amide or solvate or hydrate thereof.

In another aspect, the present invention provides a process for preparing (2R) -2 - [[(4 - chlorophenyl) sulfonyl] [[2 - fluoro -4 - (1,2,4 -

oxadiazol-5 - deuterium -3 - yl) phenyl] methyl] amino] -5,5,5 - trifluoro-pentyl amide method comprises the steps of (R) -2 - (4 - chlorophenylsulfonylamino) -5, 5,5 - trifluoro-pent-amide and 3 - (4 - (bromomethyl) -3 - fluorophenyl) -5 - deuterium -1,2,4 -

diazole in an inert organic solvent at a base (preferably an inorganic base , for example, cesium carbonate) in the reaction.

In yet another aspect, the invention provides a process for preparing (2R) -2 - [[(4 - chlorophenyl) sulfonyl] [[2 - fluoro -4 - (1,2,4 -

oxadiazol-5 - deuterium -3 - yl) phenyl] methyl] amino] -5,5,5 - trifluoro-pentyl amide, comprising the steps of:

(a) (R)-2-(4-chloro-N-(4-cyanic acid-2-luorobenzyl) phenyl sulfonamido)-5,5,5-trifluoro valeramide and azanol reaction and

(b) (the R)-2-of Xing Chenging (4-chloro-N-(2-fluoro-4-(N'-hydroxy formamidine base) benzyl) phenyl sulfonamido)-5,5,5-trifluoro valeramide and triethyl orthoformate-D be reaction in the presence of acid catalyst in inert organic solvents.

Because The compounds of this invention has unsymmetrical carbon, thus the present invention includes the racemoid and the discrete enantiomeric forms of formula I compound, and chirality as described herein and racemic intermediate.Use single symbol for example (R) or (S) comprise most of single stereoisomers.Mixture of isomers can be according to currently known methods, and for example fractional distillation, adsorption chromatography or other suitable separation method are separated into the discrete isomer.The racemoid that forms can be after introducing suitable salt forming group; Mode with common separates into enantiomorph, for example, forms the mixture of diastereomeric salt with the salt forming agent of opticity; This mixture separation is become diastereomeric salt, and isolated salt is changed into free cpds.Enantiomeric forms also can be carried out fractional separation via chirality high pressure liquid chromatography post.Should be understood that the adding of deuterium can be used symbol " D " in chemical formula or reaction scheme, " d " or " ²H " indication.

In the method for the invention, term " treatment significant quantity " refers to the total amount of each active ingredient in the method, and this quantity is enough to demonstrate significant patient and benefits, and, cures the illness relevant with beta amyloid peptide that is.When indivedual activeconstituents of being applied to use separately, this term refers to this independent component.When being applied to the combination of component, this term refers to the resultant of each activeconstituents that produces curative effect, uses or uses simultaneously no matter they are co-administered, orders." treatment " speech that in this paper and claim, uses refers to prevention, delays, inhibition or alleviation and beta amyloid peptide diseases associated.

In another embodiment of the present invention, formula I compound can with in treatment/prevention/inhibition or alleviate the other medicines that formula I compound uses in effective disease or the symptom it and unite use.These other medicines can simultaneously or in a sequence be used with its normally used quantity and The compounds of this invention through certain approach.When formula I compound and one or more other medicines use simultaneously, preferably use the pharmaceutical composition that except that formula I compound, also contains these medicines.Therefore, pharmaceutical composition of the present invention comprises those compositions that also contain one or more other activeconstituentss except that formula I compound.Can with for example (2R)-2-[[(4-chloro-phenyl-) alkylsulfonyl] [[2-fluoro-4-(and 1,2,4-

Diazole-5-deuterium-3-yl) phenyl] methyl] amino]-5; 5; The associating of 5-trifluoro valeramide; Use respectively or in same pharmaceutical composition, use; The instance of other activeconstituents in order to the treatment alzheimer's disease comprises; But be not limited to: as one type of medicine of anticholinesterase, for example E2020 (Aricept ), the bright (Exelon of Li Fansi ), lycoremine (Reminyl , claim Razadyne at present ); As the other medicines of nmda antagonist, memantine (Namenda for example ) and PDE4 suppressor factor, for example cilomilast (Ariflo ); The NSAID class, for example dextrorotation flurbiprofen (Flurizan ); The statins of decreasing cholesterol, for example Pravastatin, Simvastatin and atorvastatin; Anti-amyloid and anti-A β immunotherapy; The compound that suppresses the A beta peptide aggregation, for example scyllo-inositol and Iodochlorhydroxyquin; Suppress or regulate other compound of A β generation or processing, for example inhibitors of gamma-secretase, beta-secretase inhibitor, gamma secretase modulators, A β conditioning agent and GSK-3 suppressor factor; Regulate the compound that A β transforms, for example the PAI-1 suppressor factor; Regulate the compound of tau protein phosphorylation, for example GSK-3 and CDK-5 suppressor factor; PPAR _γAgonist, for example rosiglitazone; Regulate the compound of conversion of tau (τ) or phosphorylation tau protein or oligomerization, for example HSP90 suppressor factor, hdac inhibitor and anti-tau protein immunotherapy; And stabilize microtubules albumen or with its bonded compound, for example Taxane derivative and epoxy gather the tubulin derivative; With the compound of regulating mitochondrial function, for example Dimebon.

When the treatment cancer, The compounds of this invention can use with known anticarcinogen or methods of treatment.These medicines and methods of treatment comprise the reagent at cytotoxic agent/cytostatics, androgen receptor modifier, estrogenic agents, retinoid receptor conditioning agent, prenyl protein transferase inhibitor, angiogenesis inhibitor, the interference cell cycle outpost of the tax office, and radiotherapy.In addition, The compounds of this invention can be used to treat Immunological diseases, for example lupus.

Above medicine can use according to the for example quantity shown in Physician ' the s Desk Reference (PDR) (in available situation) when uniting use with The compounds of this invention, is perhaps determined by those of ordinary skill in the art.

But, should be understood that the actual compound quantity of using should be decided according to relevant environment by the doctor; This comprises the illness of being treated, the compound that selection is used, selected route of administration; Concrete patient's age, body weight and response, and the severity of patient's symptom.

General reaction scheme

The compounds of this invention can prepare according to the many different mode that organic synthesis field professional is known.Formula I compound can be used the method preparation of describing among the following reaction scheme 1-5.The reasonable change of said step is with to the conspicuous synthesis method of this area professional, all within the scope of the present invention.

Reaction scheme 1

Figure 2010800122954100002DEST_PATH_IMAGE007

In the preparation method shown in the reaction scheme 1; (alpha-amido) acetamide of starting material formula II is with enantiomeric pure form use basically; It can prepare with the literature method of knowing; For example utilize in reaction scheme 3 the asymmetric Strecker synthetic method of describing that is used for the trifluoro butyraldehyde is transformed (alpha-amido) acetamide of accepted way of doing sth II; Or from (R)-5; 5; 5- trifluoro norvaline (is seen I.Ojima; J.Org.Chem.(1989) 54:4511-4522) and method described in the reaction scheme 4 set out; Then utilize the general step of acid amides preparation: R.C.Larock " ComprehensiveOrganicTransformations; VCHPublishers; NewYork; 1989, pp.972-976.With (alpha-amino group) ethanamide of formula II with suitable alkaline purification, and at suitable aprotic solvent such as CH ₂Cl ₂In under about room temperature, use the sulfonation of chlorine SULPHURYL CHLORIDE, obtain (α-sulfonamido) ethanamide of formula III.Suitable alkali comprises triethylamine, diisopropylamine, pyridine etc.

A compound of formula III to the sulfonamide of formula IA into a base of formula III in the presence of (α-sulfonamido) acetamide of the formula IV in deuterated

oxadiazol fluorobenzyl alkylating agent in a suitable aprotic solvent with or without heating the reaction to proceed.Formula IV fluorobenzyl deuterated

easy to use oxadiazole prepared by methods known in the art wherein X is a leaving group, or by using the method described in Reaction Scheme 6 was prepared.The alkali that is fit to this alkylated reaction comprises mineral alkali, for example salt of wormwood and cesium carbonate.Preferred solvent comprises DMF and acetonitrile.The temperature range of reaction generally is 20 ℃ to 100 ℃.

Reaction scheme 2

Figure 2010800122954100002DEST_PATH_IMAGE009

In the reaction shown in Scheme 2 Another method for preparing a compound of formula IA, 1,2,4 -

diazole compound of formula VI by using a 2 - cyano-4 - fluoro-benzyl derivatives (wherein X is a leaving group group) in a suitable solvent in the presence of a base alkylating a compound of formula III to give the nitrile of formula VII.Then from the nitrile of formula VII; The method of knowing with this area professional (referring to: Joule; J. A. etc.; Heterocyclic Chemistry; The 3rd edition; Chapman Hall, London (1995) 452-456 and the reference of wherein quoting), prepare desired formula I-A compound.For example; The nitrile of formula VII and azanol react under the temperature that is up to backflow in alcoholic solvent (for example methyl alcohol or ethanol); Obtain the midbody acid amide oxime, it use subsequently deutero ortho-formiate (for example triethyl orthoformate or trimethyl-D) in the presence of acid source (for example trifluoroacetic acid or boron trifluoride-ether complex) in inert organic solvents (CH for example ₂Cl ₂, acetonitrile, tetrahydrofuran (THF) etc.) in handle, obtain 1,2 of formula I-A, 4-

Diazole.

Reaction scheme 3

Reaction scheme 3 has been described the preparation of formula II's (alpha-amino group) ethanamide: from commercially available trifluoro butyraldehyde with (R)-α-Jia Jibianji amine; Under the Strecker condition that contains acetate and cyanide source (like sodium cyanide, potassium cyanide or cyaniding trimethyl silane); Reaction in suitable solvent (for example methyl alcohol); Obtain the amino-nitrile of formula VIII, be the mixture of diastereomer.Initiator trifluoro butyraldehyde also can prepare through three fluoro butanol oxidations.The acid amides that the nitrile of formula VIII is hydrolyzed into corresponding formula IX carries out with sulfuric acid; Reaction mixture is neutralized; Acidifying subsequently and from suitable solvent (for example methyl alcohol, Virahol, ethyl acetate, methyl tertiary butyl ether or its mixture) recrystallization, with>99% diastereomeric excess obtains the acid amides of formula X.Can in the presence of suitable catalyst (for example palladium hydroxide or carbon carry palladium), remove benzyl through hydrogenation then, obtain the amino amides of formula II, it is available carries out sulfonylation to the chlorine SULPHURYL CHLORIDE, obtains the sulphonamide of formula III.

Reaction scheme 4

Figure 2010800122954100002DEST_PATH_IMAGE013

In another preparation method, (alpha-amino group) ethanamide of formula II can utilize enzymatic means, and from 5,5,5-three fluoro-2-oxopentanoic acids set out, Stereoselective preparation shown in reaction scheme 4.(R)-5,5 of formula XIV, the method that 5-trifluoro norvaline can utilize this area professional to know is used commercially available (R)-transaminase, from formula XIII compound with the prepare of enantiomer-pure basically.In another approach, this enzymatic means can use commercially available (R)-amino acid dehydrogenase to carry out.Enzymatic means is to carry out with the method that the method that describes below and this area professional are known.(R)-5,5 of formula XIV, 5-trifluoro norvaline can carry out with the general step that is used for the acid amides preparation well-known in the art to formula II conversion of compounds.

Reaction scheme 5

Figure 2010800122954100002DEST_PATH_IMAGE015

The bromotoluene of formula VIa can use initiator (for example AIBN) to carry out bromination through commercially available 2-fluoro-4-cyanic acid toluene in suitable solvent (for example methylene dichloride, ethylene dichloride or tetracol phenixin) with the N-bromo-succinimide and prepare shown in reaction scheme 5.Bromination reaction carries out with high yield, and if desired, the method that formula VIa compound is known with this area professional easily transforms accepted way of doing sth VI compound, and wherein X is a leavings group.

Reaction scheme 6

In the above reaction scheme 2 as described in the preparation of formula IA sulfonamide

linear sequence diazole compound of formula VI using an alternative reaction scheme 6 illustrates the preparation of compounds of formula IV, which can be used in the reaction described in Scheme 1 together type synthetic route.Commercially available 2-fluoro-4-cyanic acid toluene is at room temperature handled in alcoholic solvent with azanol, obtains the amidoxime crude product of formula XI, and it can directly be used for subsequent reaction.Amide oxime of formula XI with boron trifluoride - diethyl ether complex and triethyl orthoformate-D processing to achieve cyclization to give the formula XII

oxadiazole, two-step yield of 90%.As the alternative method of using boron trifluoride, this cyclization also can be accomplished as acid source through using trifluoroacetic acid neatly.In a suitable solvent (such as dichloromethane, methylene chloride or carbon tetrachloride) using N-bromosuccinimide and an initiator (eg AIBN) bromination, a bromide of formula IVa deuterated

two azole compounds.If hope to avoid the possible monobromide and the mixture of dibromide; Can be wittingly with N-bromo-succinimide and AIBN with the excessive bromination of toluene functional group of formula XI compound to obtain corresponding dibromide; It can reduce with diethyl phosphite subsequently, obtains the monobromide of formula VIa with the yield more than 90%.This dibrominated reaction can be accomplished in single still with reduction reaction and needn't separate dibromide, and total recovery surpasses 90%.Or; Formula IVa compound also can be prepared in suitable two phase solvent system (for example ethyl acetate/water, methylene dichloride/water, butylacetate/water, phenylfluoroform/water etc.) by formula VII compound and excessive sodium bromate and sodium bisulfite; Obtain the mixture of monobromo and dibromide intermediate; It with diethyl phosphoric acid/diisopropylamine in-situ reducing, is obtained the monobromide of formula IVa.If desired, the method that formula IVa compound is known with this area professional easily transforms accepted way of doing sth IV compound, and wherein X is a leavings group.

Reaction scheme 7

As conspicuous to this area professional, D atom can be spiked in the various initiators that in preparation I compound, use.For example, in the sulfonylation of amino amides II, use the SULPHURYL CHLORIDE of the one or more D atoms of admixture can obtain deuterated sulphonamide III-d, it can be used for preparing the formula I-B compound shown in the scheme 7.These methods can be used to combine one or more D atoms in the desirable position of formula I compound.DE 10162121A1 provide 2,3,5, the synthesis method of 6-four deuteriums-4-chlorobenzene sulfonyl chloride, and it can be used for preparation deutero formula I compound on the sulphonamide phenyl ring.

In another embodiment, the present invention includes the pharmaceutical composition that contains with pharmaceutical adjuvant, carrier or thinner bonded formula I compound.

In yet another embodiment; The present invention relates to a kind of treatment has in the Mammals that needs for the method that suppresses the responsive disease of beta amyloid peptide, and this method comprises formula I compound or its solvate or the hydrate to said administration treatment significant quantity.

In another embodiment; The present invention relates to a kind of method of in the patient who needs is arranged, treating, alleviating or delaying the outbreak of following disease: alzheimer's disease, cerebral amyloid angiopathy, systemic amyloidosis, the hereditary cerebral hemorrhage with Dutch type amyloidosis, multi infarct dementia, mild cognitive damage and Down's syndrome, this method comprises to the formula I compound of said patient's administering therapeutic significant quantity or its solvate or hydrate.

In another embodiment, the present invention relates to be used to treat the method for a wound, traumatic brain injury and/or boxer's dementia, this method comprises formula I compound or its solvate or the hydrate to the administration treatment significant quantity that needs are arranged.

In yet another embodiment, the present invention relates to be used to treat the method for a wound, comprise formula I compound or its solvate or hydrate to the administration treatment significant quantity that needs are arranged.

In another embodiment, the present invention relates to be used to treat the method for traumatic brain injury, comprise formula I compound or its solvate or hydrate to the administration treatment significant quantity that needs are arranged.

In yet another embodiment, the present invention relates to be used to treat the method for boxer's dementia, comprise formula I compound or its solvate or hydrate to the administration treatment significant quantity that needs are arranged.

Use for treatment; The pharmaceutically active compounds of formula I can adopt standard and the administered of technology routine with pharmaceutical composition usually; Wherein contain as at least a this compounds of primary activity composition one of (or) and with pharmaceutically acceptable carrier of its bonded solid or liquid, and optional pharmaceutically acceptable assistant agent and the vehicle that exists.

Pharmaceutical composition comprise be fit to oral, enteron aisle outer (comprising subcutaneous, intramuscular, intracutaneous and intravenously), the formulation of transdermal, hypogloeeis, segmental bronchus or intranasal administration.So, if use solid carrier, then preparation can be by compressing tablet, place hard gelatin capsule with powder or pill form, or lozenge or rhombus lozenge form.Solid carrier can comprise conventional vehicle, for example tackiness agent, filler, compressing tablet lubricant, disintegrating agent, wetting agent etc.If desired, tablet can be used the routine techniques coating.Oral preparations comprises the push style capsule of processing with gelatin, and the soft capsule of the sealing of being processed by gelatin and coating (for example glycerine or sorbyl alcohol).The push style capsule can be equipped with and filler or tackiness agent (for example lactose or starch), lubricant (for example talcum powder or Magnesium Stearate) and the optional stablizer blended activeconstituents that exists.In soft capsule, active compound can be dissolved or suspended in the suitable liquid (for example fatty oil or liquid macrogol), adds or do not add stablizer.If use liquid phase carrier, preparation can be the forms of syrup, emulsion, soft gelatin capsule, aseptic parenteral solution, water or non-water liquid phase suspensoid, perhaps can be the drying products that is used for before use with water or other suitable carrier fluid reconstruct.Liquid preparation can contain conventional additive, for example suspension agent, emulsifying agent, wetting agent, non-aqueous carrier (comprising edible oil), sanitas, and flavouring and/or tinting material.For the enteron aisle external administration, carrier fluid comprises sterilized water usually, is most of at least, though also can use salt brine solution, glucose solution etc.Also injectable suspensoid can be used, conventional suspension agent can be used in this situation.Conventional sanitas, buffer reagent etc. also can be added to outside the enteron aisle in the formulation.For part or nose administration, in preparation, use the penetration agent or the permeate agent of the suitable concrete barrier that will penetrate.These penetration agents are generally known in the art.Pharmaceutical composition is with the routine techniques preparation of the target formulation that is fit to contain suitable quantity activeconstituents (that is formula I compound of the present invention).For example referring to, Remington ' s Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, the 17th edition, 1985.

For the dosage that reaches the required formula I compound of curative effect not only with relevant with factors such as sex and application methods such as patient's age, body weight, suppress degree and formula I compound for the related concrete obstacle or the usefulness of disease but also depend on desired A β.Also the dosage of considering treatment and formula I compound can be used with unit dosage, and this unit dosage should correspondingly be regulated with reflection relative reactivity level by this area professional.Concrete dosage (and medication every day number of times) about adopting is decided in its sole discretion by the doctor, and can be through the dose titration change to every invention particular case, to produce desirable curative effect.

For the Mammals that suffers from or suffer from probably the relevant illness of the generation with A β peptide as described herein; Comprise the people; The appropriate dose of formula I compound or its pharmaceutical composition generally is: when the enteron aisle external administration, per daily dose is about 0.01-10 mg/kg, is preferably about 0.1-2 mg/kg.When oral administration, dosage can be about 0.01-20 mg/kg, is preferably 0.1-10 mg/kg body weight.Activeconstituents is preferably to wait dosage to take 1 to 4 time every day.But, often use a low dose, increase dosage then gradually, until the optimal dose of confirming for the host who is treated.According to good clinical practice, the concentration level of the The compounds of this invention of preferably using can produce effective anti-amyloid effect, and can not cause any harmful or unsuitable side effect.Yet; Should be understood that; The actual compound quantity of using should be by the doctor according to relevant environment, comprise the illness of being treated, select compound, the route of administration of selection, each patient's age body weight and the response of taking, and the severity of patient's symptom etc. decides.

Biological data

Pharmacology in vitro

Suppress the formation of A β in the culturing cell

The H4 APP751 SWE clone 8.20 that use is cultivated in Bristol-Myers Squibb company, the H4 glioma cell line of Sweden's varient of a kind of stably express APP751, test compound in cell to the restraining effect of A β 42.Cell gone down to posterity weekly with the extent of dilution of 1:20 cultivate 2 times to remain on logarithmic phase.For IC ₅₀Measure 30 μ L cells (1.5 * 10 that will be in the DMEM substratum that contains 0.0125% BSA (Sigma A8412) ⁴Cells/well) directly implantation contains in the 384 hole compound plates (Costar 3709) of the serial dilutions of 0.1 μ L compound in DMSO.At 5% CO ₂With 37 ℃ of following incubations after 19 hours, with plate of short duration centrifugal (1000 rpm, 5 minutes).Through dilution in containing the 40 mM Tris-HCl (pH 7.4) of 0.2% BSA, prepare fresh mixtures of antibodies and be added in the test board.Measure for A β 42, will for the special antibody of A β 42 new epi-positions (565, Bristol-Myers Squibb; (Perkin Elmer) puts together with Wallac reagent) and antibody (26D6, the SIBIA/Bristol-Myers Squibb special to the N-terminal sequence of A β peptide; Put together with APC (Perkin Elmer)) mix, in each hole of culturing cell plate, add 20 these mixtures of μ L, reaching ultimate density is every hole 0.8 ng 565 and every hole 75 ng 26D6.To contain the test board foil sealing of antibody, be incubated overnight at 4 ℃.With Viewlux counter (Perkin Elmer) measured signal, in CurveMaster, utilize fitting of a curve to confirm IC ₅₀Value (based on the Excel match).

(2R) -2 - [[(4 - chlorophenyl) sulfonyl] [[2 - fluoro -4 - (1,2,4 -

oxadiazol-5 - deuterium -3 - yl) phenyl] methyl] amino] -5,5,5 - trifluoro-pentyl amide H4-8Sw effectively inhibited the formation of cells Aβ42.Analysis obtains, and suppresses IC for A β 42 ₅₀=0.12 ± 0.01 nM (mean value ± SD, n=2).

These results demonstrate that, (2R) -2 - [[(4 - chlorophenyl) sulfonyl] [[2 - fluoro -4 - (1,2,4 -

oxadiazol-5 - deuterium -3 - yl) phenyl ] methyl] amino] -5,5,5 - trifluoro-pentyl amides are effective γ-secretase inhibitors.These results support the (2R) -2 - [[(4 - chlorophenyl) sulfonyl] [[2 - fluoro -4 - (1,2,4 -

oxadiazol-5 - deuterium -3 - yl) phenyl] methyl] amino] -5,5,5 - trifluoro glutaramic as therapeutic agents for Alzheimer's disease, head trauma, traumatic brain injury, boxers dementia and / or β-amyloid peptide related to other illness.

Provide following examples and illustrate as an example, do not think that they limit the present invention by any way,, can make change invention because within spirit of the present invention.

The application's compound can prepare with the several different methods that organic synthesis field professional knows.The application's compound can be with known synthesis method in method that describes below and the synthetic organic chemistry field, or their modification that this area professional is understood is synthesized.The method that preferable methods includes, but not limited to describe below.All reference of quoting in the literary composition are all to be incorporated herein with reference to the mode of quoting in full.

Reaction and technology preparation that The compounds of this invention can use this part to describe.Reaction is at suitable agents useful for same and material, and carries out in the solvent of the conversion that is suitable for being carried out.In addition, in the description of following synthesis method, be understood that; All reaction conditionss of being advised; Comprise choice of Solvent, reaction atmosphere, temperature of reaction, duration of experiment and post-processing step, all be selected to the standard conditions of this reaction, one of skill in the art should discern easily.The professional in organic synthesis field will appreciate that the functional group who exists on the various piece of molecule must be compatible with reaction with proposed reagent.These restrictions compatible with reaction conditions to substituting group are that this area professional is conspicuous, must use other alternative method at that time.

The explanation of specific embodiments

In following examples, all temperature are degree centigrade.Fusing point is not proofreaied and correct with Thomas Scientific Unimelt capillary melting point apparatus record.Proton resonance ( ¹H NMR) spectrum is measured with Bruker Avance 300, Bruker Avance 400 or Bruker Avance 500 spectrometers.All spectrograms all shown in solvent in measure, chemical shift is with the δ unit representation of the low field orientation of the interior mark tetramethylsilane of distance (TMS), coupling constant is represented with He Zhi (Hz) between proton.Multiple graphics is represented as follows: s, and unimodal; D, bimodal; T, three peaks; Q, quartet; M, multiplet; Br, broad peak; Dd, doublet of doublet; Brd, wide bimodal; Dt, dual three peaks; Br s, wide unimodal; Dq, dual quartet.The INFRARED SPECTRUM (IR) of using Potassium Bromide (KBr) or sodium-chlor film with Jasco FT/IR-410 or Perkin Elmer 2000 FT-IR spectrographs from 4000 cm ^-1Survey to 400 cm ^-1, according to 1601 cm-1 absorption corrections of polystyrene film, with centimetre inverse (cm ^-1) expression.Specific rotation [α] _DWith Rudolph Scientific Autopol IV polarimeter shown in measure in the solvent; Concentration is represented with mg/mL.Low Resolution Mass Spectra (MS) and apparent molecular weight (MH ⁺) or (M-H) ⁺Measure with Finnegan SSQ 7000.High resolution mass spectrum is measured with Finnegan MAT 900.Liquid chromatography (LC)/mass spectrum is measured with a Shimadzu LC with Water Micromass ZQ coupling.

Adopt following dummy suffix notation: DMF (dimethyl formamide); THF (tetrahydrofuran (THF)); DMSO (dimethyl sulfoxide (DMSO)); Leu (leucine); TFA (trifluoroacetic acid); MTBE (methyl tertiary butyl ether); DAST (diethylaminosulfur trifluoride); HPLC (high pressure liquid chromatography); Rt (room temperature); Aq (aqueous); AP (area percent).

Prepare routine A

(R)-and 2-amino-5,5,5-trifluoro valeramide hydrochloride

Steps A. 4,4,4-trifluoro butyraldehyde

In the 20 L four-hole round-bottomed flasks of being furnished with mechanical stirrer and cooling bath, add methylene dichloride (4.2 L).Begin to stir and reaction mixture is cooled to 0 to-2 ℃.Add 4,4,4-three fluoro butanols (750.0 g) further are cooled to reaction mixture-5 to-8 ℃.Add TEMPO (2,2,6,6-tetramethyl--1-piperidine NO free radical) (9.15 g), maintain the temperature at-5 to-8 ℃ simultaneously.In above solution, add kbr aqueous solution (60 g are in 1.17 L water), temperature is remained on-5 to-8 ℃.When the temperature that keeps reaction mixture be-5 ℃, to wherein add (carefully heat release) NaOCl aqueous solution (8.8 L, 6-7% weight, with sodium bicarbonate buffer to pH=8.5).Similarly, can use sodium periodate (NaIO ₄) replace NaOCl as oxygenant.Isolate dichloromethane layer after adding, water layer is washed with methylene dichloride (1 * 750 mL).Dichloromethane layer is merged, use anhydrous sodium sulfate drying.Leach siccative, measure 4,4 with NMR, the concentration of 4-trifluoro butyraldehyde solution.The solution that contains title compound is not for further processing, and directly is used for next step.

Step B. 5,5,5-three fluoro-2-(the 1-styroyl is amino) valeronitrile (non-enantiomer mixture)

Under nitrogen atmosphere, R-α-Jia Jibianji amine (528.5 g) packed into and be furnished with in the suitable vessel of mechanical stirring and cooling bath.Add 4,4 successively, 4-trifluoro butyraldehyde solution (steps A, 550 g) and methyl alcohol (3.3 L).Then reaction mixture is cooled to about 0 to-3 ℃.Dropwise add glacial acetic acid (260 mL), maintain the temperature at about 0 ℃, then in 15 minutes, add cyaniding trimethyl silane (581 mL).Similarly, can use sodium cyanide (NaCN) or potassium cyanide as cyanide source.Reaction mixture is warmed to 25 to 27 ℃ and stir overnight.Confirm to react completely with TLC.In reaction mixture, add cold water (10.0 L), extract with methylene dichloride (1 * 10.0 L).Dichloromethane layer water (2 * 10.0 L) is washed, and uses salt solution (1 * 5.0 L) to wash subsequently.With the dichloromethane layer anhydrous sodium sulfate drying, concentrating under reduced pressure obtains title compound amino-nitrile (non-enantiomer mixture), is thick liquid, average yield 90%.

Step C. 5,5,5-three fluoro-2-(the 1-styroyl is amino) valeramide (non-enantiomer mixture)

With 5,5,5-three fluoro-2-(the 1-styroyl is amino) valeronitrile (non-enantiomer mixture that step B is rough, 1.10 kg) is dissolved under nitrogen atmosphere in the methylene dichloride (5.5 L) in the suitable vessel of the ice bath of being furnished with mechanical stirring, cooling usefulness.Begin to stir, reaction mixture is cooled to 0 to-5 ℃.Dropwise add the vitriol oil (1.75 L) and kept temperature to be lower than 0 ℃ in the introversive above mixture in 1 hour, obtain transparent solution after adding.The temperature of reaction mixture is risen to 25 to 27 ℃ and stir overnight (12-14 hour).Confirm to react completely with HPLC.Reaction mixture slowly is poured on the trash ice (about 15.0 kg), neutralizes with ammoniacal liquor (about 25% volume).Separating water layer also extracts with methylene dichloride (2 * 3.0 L).The dichloromethane layer water (1 * 12.0 L) that merges is washed, and uses salt solution (1 * 3.0 L) to wash then.The organic layer of enriched product obtains the rough title compound of 0.85 kg (72.0%) with dried over sodium sulfate and concentrating under reduced pressure.

Step D. (R)-5,5,5-three fluoro-2-((R)-1-styroyl is amino) valeramide hydrochloride

With 5,5,5-three fluoro-2-(the 1-styroyl is amino) valeramide (mixture of diastereomer) (850 g) is packed into and is furnished with in the suitable vessel of mechanical stirring and cooling bath.Add methyl alcohol (2.55 L), ethyl acetate (1.7 L) and water (1.06 L), reaction mixture is cooled to 0 to 5 ℃.Dropwise add the solution (4.5 Ms, 1.72 Ls) of HCl in dioxane in 30 to 45 minutes.Similarly, the mixture that can use Virahol and methyl tertiary butyl ether is as solvent, and the HCl aqueous solution or concentrated hydrochloric acid can be used as the HCl source.Then the temperature of reaction mixture is risen to 25 to 27 ℃ and stirred 2 hours.Confirm to react completely with TLC.Leach precipitated solid, filter cake is washed with suitable solvent, for example uses ethyl acetate (1.8 L) and sherwood oil (2.5 L) to wash successively, or washes with the mixture of Virahol and methyl tertiary butyl ether.Solid is dry under envrionment temperature in open trays, obtain title compound R-amino amides (diastereomer is excessive for 480 g, yield 50%=99.9%).

Step e. (R)-2-amino-5,5,5-trifluoro valeramide hydrochloride

In suitable pressurized vessel, add (R)-5,5,5-three fluoro-2-((R)-1-styroyl is amino) valeramide hydrochloride (1.50 kg) and methyl alcohol (15.0 L).Add water (701.0 mL) subsequently, then add 20% palladium hydroxide/carbon (225 g).Similarly, can use palladium/carbon (Pd/C) as hydrogenation catalyst.Container with nitrogen purge 3 times, is pressed into hydrogen (3-4 kg/cm at 60 ℃ then in container ²).Accomplish with the HPLC monitoring reaction.After reaction is accomplished, reaction mixture is cooled to 30-35 ℃, filter through Celite pad, wash with methyl alcohol then.Filtrate decompression is concentrated.After concentrate accomplishing, the reaction mixture that stays is handled (wash at every turn and use 2.5 L) with methylene dichloride, 45 ℃ of dryings 12 hours, obtains title compound (915 g, 91% after filtering; Purity=97%).

Prepare routine B

(R)-5,5,5-trifluoro norvaline

Method A. R-transaminase (Biocatalytics and BMS transaminase)

To in 0.1 M potassium phosphate buffer (pH 7.5), contain 5; 5; 5-three fluoro-2-oxopentanoic acid (100 mg; 0.588 mmol), R; S-L-Ala (200 mg; 2.244 mmol) with the solution of 0.02 mM pyridoxal phosphate and R-transaminase AT-103 (5 mg that derive from Biocatalytics; 44 units) or derive from the clone's of Tribactur SC 16569 R-transaminase (0.5 mL; 10 units, the BMS transaminase) cultivated 44 hours in 30 ℃ in 15 mL pipe with the cumulative volume of 5 mL.(R)-5,5, the reaction yield of 5-three fluoro-2-aminovaleric acids reaches 49% and 48% respectively with AT-103 and BMS transaminase the time.The ee of two kinds of situations is 100%.

The adding coenzyme makes pyruvic acid be reduced into lactic acid can improve productive rate.Lactic dehydrogenase enzyme require NADH is as cofactor.Use hydrogenlyase to make NADH regeneration.To in 0.1 M potassium phosphate buffer (pH 7.5), contain 5; 5; 5-three fluoro-2-oxopentanoic acid (100 mg; 0.588 mmol); D; L-L-Ala (200 mg; 2.244 mmol); 0.02 mM pyridoxal phosphate; Sodium formiate (68 mg; 1 mmol); NAD (3.31 mg; 5 μ mol); L-serum lactic dehydrogenase (Biocatalytics LDH-103 by the rabbit muscle clone; 0.107 mg; 15 units) and hydrogenlyase (0.5 mL; 15 units; The clone is from the pasteur pichia yeast and be expressed in the intestinal bacteria) solution and the R-transaminase (0.5 mL, 10 units) that derives from the R-transaminase AT-103 (5 mg, 44 units) of Biocatalytics or derive from the clone of Tribactur SC16569 with the cumulative volume of 5 mL in 15 mL pipe in 30 ℃ of cultivations.(R)-5,5, the reaction yield of 5-three fluoro-2-aminovaleric acids reaches 94% and 91% respectively for AT-103 and BMS transaminase.The ee of two kinds of situations is 100%.

Method B. (R)-amino acid dehydrogenase (Biocatalytics and BMS)

Step 1: with 5,5,5-three fluoro-2-oxopentanoic acids (60.00 g, 0.353 mol), NH ₄Cl (64.19 g, 1.2 mol), glucose (86.4 g, 0.479 mol) and water (975 mL) join in the reactor of one 2 L jacketed.Add NaOH (36 mL, 10 N), mixture is made the solid dissolving with magnetic stirrer 30 ℃ of stirrings, pH is about 7.Add Na ₂CO ₃(12.72 g, 0.12 mol) makes pH rise to about 8.5.Add successively then NADP (458 mg, 0.60 mmol), Hexose phosphate dehydrogenase (33.7 mg, 5277 units derive from Amano Enzyme Company) and R-amino acid dehydrogenase (600 mg D-AADH-102, Biocatalytics).Dropwise adding 10 N NaOH makes the pH of reaction mixture rise to 9.Reaction mixture stirred and add 5 N NaOH with permanent pH titration apparatus at 30 ℃ maintain pH 9.00.This solution generates 51.1 g (R)-5,5 after 21 hours, 5-three fluoro-2-aminovaleric acids, yield 84.7%, 100% ee.

Step 2: with 5,5,5-three fluoro-2-oxopentanoic acids (60.00 g, 0.353 mol), NH ₄Cl (64.19 g, 1.2 mol), glucose (86.4 g, 0.479 mol) and water (975 mL) are packed in the reactor of 2 L jacketed.Add NaOH (36 mL, 10 N), mixture is stirred in 30 ℃ of stirrings with magnetic makes the solid dissolving, pH is about 7.Add Na ₂CO ₃(12.72 g, 0.12 mol), this makes pH rise to about 8.5.Add NADP (458 mg, 0.60 mmol), Hexose phosphate dehydrogenase (33.7 mg, 5277 units, Amano Enzyme Company) and D-amino acid dehydrogenase (50 mL extracts contain 1500 units, the BMS enzyme) successively.Reaction mixture is faded to pH 9 through dripping 10 N NaOH.It 30 ℃ of stirrings, and is remained on pH 9.00 with the constant appearance of pH through adding 5 N NaOH.This solution produces 51.04 g (R)-5,5 after 15 hours, 5-three fluoro-2-aminovaleric acids, yield 84.6%, 99.1% ee.

Prepare routine C

4-(brooethyl)-3-fluorobenzonitrile

Method A. NBS/AIBN bromination

With 1,2-ethylene dichloride (151 kg) is in 4-cyanic acid-2-toluene fluoride (24 kg) and AIBN (2 kg) suitable containers of packing into.With mixture heating up to 70 to 74 ℃.Reach 70 ℃ in case bathe temperature, just the speed with 12 kg/h adds N-bromo-succinimide (47.4 kg) in batches, and maintains the temperature at 70-74 ℃ (controlling adding speed to avoid thermopositive reaction very important).After adding 24 kg N-bromo-succinimides, detect the selective examination reaction mixture by GC, and reaction mixture is reacted completely until observing 70-74 ℃ of heating.Mixture is cooled to 0-5 ℃, placed again 2 hours.Mixture is filtered, and filter cake is washed with MTBE (24 kg).(3 * 65 kg) washes with filtrate water.Organic layer dry 6 hours with sodium sulfate (10.3 kg) filters, and filter cake is washed with MTBE (24 kg).With the solution decompression evaporation, add ethanol (12 kg), mixture heating up under agitation slowly is cooled to 0-5 ℃ then and makes its crystallization to 40-45 ℃.Mixture is filtered, and filter cake is washed with cold ethanol (5 kg).Rough solid recrystallization from sherwood oil filters and washes with sherwood oil (10 kg), obtains title compound 4-(brooethyl)-3-fluorobenzonitrile, is pale solid (21 kg, yield 55%).

Method B. sodium bromate bromination

In suitable containers, add methylene dichloride (40 L) and 3-fluoro-4-methyl benzonitrile (4 kg, 18.7 mol), then add aqueous sodium bromide (13.45 kg, 89.1 mol are dissolved in the 53.6 L water).Reaction mixture is cooled to 0-5 ℃.In 2-3 hour, add sodium sulfite solution (9.25 kg are dissolved in the 42 L water), keep warm 10-20 ℃ (exothermic heat of reaction) of material simultaneously.After adding, with the light irradiation reactor of 200 W, the material temperature is increased to 25-30 ℃.Keep illumination and temperature, reach 70-75% up to HPLC indication product.Remove illumination, stop to stir, made the reaction mixture sedimentation 15 minutes.Remove organic layer, remaining water layer is with dichloromethane extraction 2 times.Organic layer is merged, wash 4 times with 10% hypo solution.Use salt solution (10 L) to wash then, use dried over sodium sulfate.Organic layer is concentrated, add sherwood oil and be distilled to and do totally twice, to remove all methylene dichloride.Add sherwood oil (3 L), with this slurry be cooled to 5-10 ℃ 1 hour.Filtering this slurry also washes with cold sherwood oil.With product in vacuum drying oven in 40-45 ℃ of drying, obtain pale solid title compound (3.2 kg, yield 50.4%).

From mother liquor, reclaim the exemplary steps of title compound: mother liquor is concentrated the crude product that obtains (about 36% 4-(brooethyl)-3-fluorobenzonitrile and about 59% together with dibromide) (300 g) and 2 normal diisopropylethylamine (to be the basis together with dibromide) are dissolved in acetonitrile (3 L) and the water (50 mL).Reaction mixture is cooled to 0-5 ℃, in 30 minutes, adds diethyl phosphite (169 g, 1.22 mol) (adding fashionable heat release).Reaction mixture is monitored at 0-5 ℃ of stirring 60-90 branch and with TLC.When TLC indication dibromide no longer exists, add water (3.3 L) and with the slurry by filtration that forms.Filter cake is with washing, dry in vacuum drying oven (until moisture content less than 1%), obtains the other a title compound of 202 g (HPLC indicates 98 AP).

Prepare routine D

(R)-and 2-(4-chloro-phenyl-sulfonamido)-5,5,5-trifluoro valeramide

Steps A. 5,5,5-three fluoro-2-(the 1-styroyl is amino) valeronitrile

Add NaCN (3.88 g, 79.6 mmol) to (R)-phenylethylamine (9.60 g, 79.4 mmol) and the solution of acetate (5.08 g, 79.6 mol) in methyl alcohol (150 mL).Reaction mixture is cooled to 0 ℃, adds 4,4, the solution of 4-trifluoro butyraldehyde (10.0 g, 79.6 mmol) in methyl alcohol (50 mL).Reaction mixture is warmed to room temperature and stirred 20 hours.Water (400 mL) diluted reaction mixture is used CH ₂Cl ₂(3 * 300 mL) extraction.The organic layer Na that merges ₂SO ₄Drying, concentrating under reduced pressure obtains amino-nitrile title compound (18.1 g, 89%, be the non-enantiomer mixture of 4:1), is light yellow oil:

Step B. (R)-5,5,5-three fluoro-2-((R)-1-styroyl is amino) valeramide hydrochloride

To 5,5,5-three fluoro-2-(the 1-styroyl is amino) valeronitrile (18.0 g, 70.31 mmol, the non-enantiomer mixture of 4:1) is at CH ₂Cl ₂Solution in (100 mL) adds H ₂SO ₄(100 mL).Reaction mixture stirring at room 22 hours, is poured on and uses NH on the trash ice ₄The OH neutralization.This mixture extracts with EtOAc (3 * 500 mL).The organic layer Na that merges ₂SO ₄Drying, concentrating under reduced pressure obtains the title compound of free alkali form, is the mixture (18.94 g, 98%) of diastereomer, orange:

Hydrochloride

To the free alkali (11.9 g, 43.4 mmol) of the title compound of non-enantiomer mixture form at Et ₂Solution among the O/MeOH (7:1,40 mL) adds the HCl/Et of 1 N ₂O solution (70 mL).With this mixture heating up and add MeOH (to final ratio be 4:1 Et ₂O/MeOH) white precipitate of formation is dissolved again.This solution is cooled to room temperature and places spend the night.The amino amides hydrochloride of title compound is white solid with the form of single enantiomer separated (3.11 g, 23%):

。

Step C. (R)-2-(4-chloro-phenyl-sulfonamido)-5,5,5-trifluoro valeramide

To (R)-5,5, the solution of 5-three fluoro-2-((R)-1-styroyl is amino) valeramide hydrochloride (3.10 g, 10.0 mmol) in EtOH (100 mL) adds Pd (OH) ₂(350 mg) and water (10 mL).With reaction mixture 50 ℃ of hydrogenations (40 psi) 4 hours.Through diatomite filtration, filtrate decompression concentrates, and obtains white solid intermediate amine hydrochloride with reaction mixture.To this amine at CH ₂Cl ₂Suspension-s in (100 mL) adds N, N-diisopropylethylamine (5.25 mL, 30.0 mmol) and 4-chlorobenzene sulfonyl chloride (2.53 g, 12.0 mmol).Stirred reaction mixture is 18 hours under the room temperature, with EtOAc (200 mL) dilution, uses NaHCO ₃(250 mL) and salt solution (250 mL) are washed, and use Na ₂SO ₄Dry also concentrating under reduced pressure.With residue CH ₂Cl ₂/ hexane (2:1) wet-milling obtains white solid title compound (2.91 g, 84%):

Prepare routine E

(R)-and 2-(4-chloro-N-(4-cyanic acid-2-luorobenzyl) phenylsulfonamido)-5,5,5-trifluoro valeramide

Steps A. 4-(brooethyl)-3-fluorobenzonitrile

Add N-bromo-succinimide (4.97 g, 0.28 mol) and AIBN (100 mg, 0.61 mmol) to the solution of 3-fluoro-4-methyl benzonitrile (5.0 g, 0.23 mol) in 100 mL tetracol phenixin, mixture was refluxed 6 hours.With reaction mixture cooling and filtration, filtrate water is washed, and uses dried over mgso, filters, and removal of solvent under reduced pressure obtains 5.44 g title compounds, is pale solid. ¹There is 20% initiator in H NMR indication.Title compound ¹H NMR (400 MHz, CDCl ₃): δ 7.54-7.30 (m, 3H), 4.83 (s, 2H).

Step B. (R)-2-(4-chloro-N-(4-cyanic acid-2-luorobenzyl) phenylsulfonamido)-5,5,5-trifluoro valeramide

To (R)-2-(4-chloro-phenyl-sulfonamido)-5,5,5-trifluoro valeramide (6.88 g, 20.0 mmol) and the solution of 4-(brooethyl)-3-fluorobenzonitrile (6.43 g, 30 mmol) in DMF (35 mL) add anhydrous Cs ₂CO ₃(19.56 g, 60 mmol).The mixture that forms at room temperature stirred 45 minutes, used EtOAc (200 mL) dilution then, and water (100 mL * 4) is washed, and uses Na ₂SO ₄Dry.With product with Biotage (40+M post, 3-80% EtOAc/ hexane, 651 mL) purifying.Obtain title compound, be white solid (6.50 g, 68.1% yield).

Prepare routine F

(R)-and 2-(4-chloro-phenyl-sulfonamido)-5,5,5-trifluoro valeramide

In suitable drying receptacle, add (R)-2-amino-5,5,5-trifluoro valeramide hydrochloride (199.52 g under the room temperature; 0.966 mol, 1.0 equivalents), then add 4-chloro-phenyl-SULPHURYL CHLORIDE (215.22 g; 0.989 mol, 1.02 equivalents, 97% w/w%) and 1.6 L THF.In 20 minutes, add triethylamine (206.5 g, 2.04 mol, 2.1 equivalents), keep the still temperature at 15-25 ℃, the white slurry of formation stirred 30 minutes at 15-25 ℃.In 20-25 ℃ of downhill reaction mixture, add water (1.4 L, 7 times of volumes), THF (1.4 L, 7 times of volumes) (in still-process, the still temperature keeps 40-60 ℃ under 250-400 mmHg) is removed in underpressure distillation then.After distillation is accomplished, in 30 minutes, add the water of 1.4 L (7 times of volumes), keep the still temperature at 50-60 ℃ simultaneously.The slurry that forms was stirred 30 fens at 50-60 ℃, be cooled to 10 ℃ then.Stir this slurry and be no less than 1 hour, leach product.Filter cake water (each 600 mL) is washed, until pH >=5 of the filter cake washing lotion of measuring.Filter cake is being no more than 70 ℃ (jacket temperatures) vacuum-drying down, and < 0.5 w/w% obtains title compound, is white solid (300 g, yield 91%) until weight loss on drying.

Embodiment 1

(2R) -2 - [[(4 - chlorophenyl) sulfonyl] [[2 - fluoro -4 - (1,2,4 -

oxadiazol-5 - deuterium -3 - yl) phenyl] methyl] amino] -5,5,5 - trifluoro-pentyl amide

Steps A. (2R)-2-[[(4-chloro-phenyl-) alkylsulfonyl] [(4-cyanic acid-2-fluorophenyl) methyl] amino]-5,5,5-trifluoro valeramide

With (R)-2-(4-chloro-phenyl-sulfonamido)-5,5,5-trifluoro valeramide (3.444 kg), salt of wormwood (2.774 kg), bromination tetrabutylammonium (0.484 kg) and 4-(brooethyl)-3-fluorobenzonitrile (2.092 kg) reactor of packing into.Add ethyl acetate (17.2 L) and water (3.44 L) then, material is heated to 50 ℃ up to HPLC Indicator Reaction fully (the relative AP of initiator < 1).Reaction was accomplished in about 15 hours usually.Material is cooled to 15-20 ℃, adds water (6.88 L), isolate bottom aqueous phase.Add sodium dihydrogen phosphate (the 0.2 M aqueous solution, 20.66 L), separate bottom aqueous phase and test pH, can add 20.66 L, 0.2 M SODIUM PHOSPHATE, MONOBASIC again, re-extract and pH determination step) to guarantee pH < 6.5 (note:>6.5 if pH.Utilize constant volume vacuum distilling with exchange of solvent then.Reactor is placed under the vacuum (270 mmHg), and chuck is heated to 75-80 ℃.In case ethyl acetate begins to distillate, just the identical speed of collecting with overhead product adds Virahol (41.34 L), and the volume of whole material remains unchanged.After adding all Virahols, discharge vacuum immediately, add water (13.76 L).During adding water, keeping temperature of charge is about 50 ℃.Then material is cooled to 15-20 ℃ and filtration.Wet cake is washed with 50% (v/v) isopropanol water solution (4 * 21.6 kg), then 50 ℃ of vacuum-dryings, obtains pale solid shape title compound (3.648 kg, yield 78%).

Step B. (R)-2-(4-chloro-N-(2-fluoro-4-(N'-hydroxy formamidine base) benzyl) phenyl sulfonamido)-5,5,5-trifluoro valeramide

With (2R)-2-[[(4-chloro-phenyl-) alkylsulfonyl] [(4-cyanic acid-2-fluorophenyl) methyl] amino]-5,5,5-trifluoro valeramide (399 g) and methyl alcohol (1.6 L) add in the reactor, add azanol (50% aqueous solution, 93 mL, 1.8 equivalents) subsequently.With mixture heating up to 45-50 ℃, until HPLC Indicator Reaction fully (the relative AP of initiator < 0.15).Slowly add entry (0.5 L) and keep the material temperature at 30-50 ℃.The material placement is begun until crystallization, add water (2.7 L) then.Material is cooled to 15-20 ℃ and filtration.Filter cake is with the methyl alcohol of 2:1: water (2 L) is washed, and then 50 ℃ of vacuum-dryings, obtains white solid title compound (415 g, yield 96%).

Step C. (2R) -2 - [[(4 - chlorophenyl) sulfonyl] [[2 - fluoro -4 - (1,2,4 -

oxadiazol-5 - deuterium -3 - yl) benzene yl] methyl] amino] -5,5,5 - trifluoro-pentyl amide

At 45 ℃ to (R)-2-(4-chloro-N-(2-fluoro-4-(N'-hydroxy formamidine base) benzyl) phenyl sulfonamido)-5; 5; 5-trifluoro valeramide (500 mg; 0.98 mmol), positive formic acid triethyl-D (175 mg; 1.2 mmol) solution in acetonitrile (5 mL) adds TEA (3.8 μ L, 0.049 mmol).Mixture 60 ℃ of heating 90 minutes, is cooled to room temperature then.Adopt identical condition; With 630 mg (1.23 mmol) (R)-2-(4-chloro-N-(2-fluoro-4-(N'-hydroxy formamidine base) benzyl) phenyl sulfonamido)-5; 5,5-trifluoro valeramide, 220 mg (1.5 mmol) triethyl orthoformate-D and 4.5 μ L (0.06 mmol) TEA repeat this reaction in acetonitrile (5 mL).Reaction mixture is merged the back evaporation, the solid that obtains with the HPLC purifying (Phenomenex Luma 100 * 30 mm, in 15 minutes from 0% MeOH-H ₂O 0.1% TEA to 100% MeOH-H ₂O 0.1% TEA), obtain white solid (950 mg, 1.82 mmol, 83%).

Residual

oxadiazole integral proton signals indicate about 1% proton isotope analogues exist.

Claims

1? Compound which is (2R) -2 - [[(4 - chlorophenyl) sulfonyl] [[2 - fluoro-4 - (1,2,4 - ?

Figure 2010800122954100001DEST_PATH_IMAGE001

oxadiazol-5 - deuterium -3 - yl) phenyl] methyl] amino] -5,5,5 - trifluoro-pentyl amide.

2? Pharmaceutical composition which contains pharmaceutically acceptable adjuvants, carriers or diluents in a therapeutically effective amount of (2R) -2 - [[(4 - chlorophenyl) sulfonyl] [[2 - fluoro- -4 - (1,2,4 -

3? Treatment or delay Alzheimer's disease, cerebral amyloid angiopathy, mild cognitive impairment and / or Down syndrome episodes, comprising administering to a mammal in need thereof a therapeutically effective amount of (2R) - 2 - [[(4 - chlorophenyl) sulfonyl] [[2 - fluoro -4 - (1,2,4 -

oxadiazol-5 - deuterium -3 - yl) phenyl] methyl ] amino] -5,5,5 - trifluoro-pentyl amide.

4. the method that is used to treat alzheimer's disease of claim 3.

5? Treatment of head trauma, traumatic brain injury and / or boxer dementia, comprising administering to a mammal in need thereof a therapeutically effective amount of (2R) -2 - [[(4 - chlorophenyl) sulfonyl] [[2 - fluoro -4 - (1,2,4 -

oxadiazol-5 - deuterium -3 - yl) phenyl] methyl] amino] -5,5,5 - trifluoro glutaramic .

6. the method that is used to treat a wound of claim 5.

7. the method that is used to treat traumatic brain injury of claim 5.

8. the method that is used to treat boxer's dementia of claim 5.